Protein non-enzymatic glycosylation process is a phenomenon identified for a long time, consisting initially in the spontaneous condensation of reducing sugars like glucose or fructose, with the N-terminal amino functions of some protein or lipoprotein constituents like lysine and arginine aminoacids. Contrarily to enzymatic glycosylation process which is genetically programmed, such a process adversely leads to irreversible changes of proteins after a result of chain reactions and of complex molecular rearrangements.
The disturbance of these changes on biological tissues and their cell components is clearly established with multiple physiological consequences: protein functional changes leading to cell metabolism dysfunctions (enzymatic activity disruptions), mechanical property changes of some support tissues, activation of inflammatory processes or of oxidative stress with production of cytokines or of oxygen reactive species, repair process impairments, etc. It is besides evidenced that such changes in proteins play an essential role in the development or speed of some pathologies notably linked to ageing, like sugar diabetes, atherosclerosis, Alzheimer and Parkinson diseases, renal failure, etc. (J. Uribarri et al., J. Gerontol. In Biol. Sci. Med. Sci. (2007), vol. 62, pp. 437-433).
Specifically as far as skin is concerned, the impact of proteins' non-enzymatic glycosylation process, in particular on aging, is undisputed. Indeed once glycated by spontaneous condensation of sugar, skin proteins and in particular those of structures such as collagen or elastin, become rigid with the accumulation of interfibre covalent cross-links. Skin visco-elastic properties are thus reduced, which increases the first signs of emerging wrinkles or already formed wrinkles. The renewal of these skin proteins is also slowed down (Dyer D.G. et al., J. Clinical Invest. (1993), vol.91, pp. 2463-9).
Another well admitted knowledge today, but not least, on protein non-enzymatic glycosylation process is that this complex process also releases some substances often referred to as “glycosylation by-products” that behave like real toxins. Besides like a recent article entitled “Glycotoxins : a possible threat to health?” (Odetti P. et al., Mediterr. J. Nutr. Metab., (2008), vol. 1, pp. 63-67), the more suggestive terminology of “glycotoxins” is more and more reported in the literature for designating the whole of deleterious products resulting from the protein non-enzymatic glycosylation process (Koschinski T. et al., Proc Natl. Acad. Sci. USA (1997), vol. 94, pp. 6474-6479). This refers to various substances poorly defined among which compounds such as glyoxal, methyl-glyoxal or deoxyglucosone can be however featured.
A characteristic of glycotoxins especially harmful to living organisms is their ability to damage cellular DNA. Indeed, such alterations can induce gene mutations responsible for a genomic instability. For example, the mutagenicity of by-products, formed when protein bovine albumin (BSA) is in vitro incubated with glucose, has been reported (Ogata M. et al., J. Clinical Biochem. Nutr.(2006) vol. 38, pp. 176-179). Several alpha-ketoaldehydes, especially the aforementioned glyoxal and methyl-glyoxal, are able to induce mutations on genes of bacterial strain and of human cells (Ueno H. et al., Mutation Res. (1991), vol. 251, pp.99-107). More recently, the genotoxic potential of glycotoxins which are likely to result from the formation of stable adducts by reaction with some DNA constitutive nucleosides, has been reported (Ahmad S., Biochem. Biophys. Res. Common. (2011), vol. 15, pp.568-74). Methyl-glyoxal thus targets particularly guanosines from DNA's nucleoside chains, hence leading to the apparition of mutations during the DNA replication process, especially in the absence of an efficient repair (Wuenschell G.E. et al., Biochemistry (2010), vol.49, pp.1814-1821).
Consequently with regard to these different statements, the applicant focused on the identification of substances, with cosmetic or dermocosmetic purpose, able to interfere with protein non-enzymatic glycosylation process with main objective to avoid any damage affecting skin cells' DNA and resulting from glycotoxin production. It is indeed currently of interest in the cosmetic industry, particularly to prevent from skin cells' premature senescence, to protect genomic DNA of cells such as keratinocytes or fibroblasts.
With this objective, the applicant more precisely searched for original structures able to trap glycosylation by-products during the protein non-enzymatic glycosylation process, like the above-described genotoxic glycotoxins, while caring about that the formed adducts (glycotoxin-trapper) are not genotoxic, but also preventing these same adducts from leading to the formation of products themselves genotoxic. It is effectively of first importance in the frame of a cosmetic or dermocosmetic purpose, besides the innocuousness of substances, also to make sure of the innocuousness of reaction by-products resulting from the targeted cosmetic activity.
Concerning the state of the art attached to the applicant's objectives, the prior art essentially reveals, to the knowledge of the applicant, substances or preparations which display a simple preventive or inhibiting profile in the glycosylation products' formation. Thus, for example, the guanidine family substances such as aminoguanidine and metformin are of therapeutic interest for their ability to bind early glycosylation by-products (Matsuki K. et al., Atherosclerosis (2009), vol. 206, pp. 434-8). Several salts of thiazolium, especially N-phenacyl thiazolium bromide or “PTB”, would also be of therapeutic interest thanks to their ability to break the crossed links between proteins (Ulrich P. et al., Diabetologia (1997), vol. 40, pp. S157-S159).
In regard to skin care, some benzofuran hydroxylated derivatives are used in cosmetic purposes for their restricting properties, even disclosed as inhibiting properties, towards the non-enzymatic glycosylation reaction of dermal or keratinic proteins (patent FR 2833165). The applicants of patents FR 2802425 and WO 2010/010248 succeeded in identifying plant extracts, respectively of Ericaceae and Sapotaceae families, for skin cell and protein protection with a same restricting or inhibiting result. But it has to be underlined that none of these documents provides in combination, information about a benefit to skin cells' DNA when specifically subjected to genotoxic glycotoxins, and information about the becoming of detoxified glycosylation by-products. More broadly, the antioxidant qualities of products with an imidazole group are also mentioned in patent application WO95/12581 filed by the applicant, these compounds being used for various therapeutic and cosmetological applications.